The discovery that persistent cervical infections by approximately 15 cancer-associated or high-risk human papillomavirus (HPV) genotypes cause virtually all cervical cancer and its immediate precursor lesions has clarified the key steps in cervical carcinogenesis: HPV acquisition, HPV persistence (vs clearance), progression to precancer, and invasion. This improved understanding of cervical carcinogenesis has led to the discovery of new diagnostic biomarkers that can be used to improve patient management in cervical cancer screening programs. Just as adjunctive HPV DNA testing can clarify the meaning of an equivocal Papanicolaou result (ie, atypical squamous cell of undetermined significance) by differentiating those at high and low risk of cervical precancer and cancer, the use of p16INK4a immunohistochemistry (p16 IHC) might be used to clarify ambiguous histologic diagnoses, specifically cervical intraepithelial neoplasia grade 2 (CIN2), which is now a recommendation from the Lower Anogenital Squamous Terminology Project. The use of p16 IHC can potentially distinguish those CIN2 that may be precancerous and need immediate excisional treatment from those who do not and can be managed less aggressively, thereby reducing the treatment of CIN2 by 25% to 30% or more.
However, there are several challenges in the implementation of p16 IHC that must be addressed, including (1) overuse, which can lead to unnecessary laboratory costs and create further clinical uncertainty with respect to patient management; (2) the potential for diagnostic drift; and (3) appropriate annotation of the diagnosis to permit the less invasive management of young women with CIN2. Monitoring of the implementation of p16 IHC in routine practice will be useful to ensure its appropriate use and to measure the benefit to the patients.